Composition for coating an implantable prosthesis

ABSTRACT

The present invention provides a method of forming a coating onto a surface of an implantable prosthesis, such as an expandable stent, a synthetic vascular graft, or some other implantable device. A composition comprising a therapeutic substance and a fluid in which the therapeutic substance has limited solubility, such that the therapeutic substance is suspended as particles in the composition, is applied to a surface of the prosthesis. The fluid is removed from the prosthesis to form a coating. A coating for a prosthesis produced in accordance with the method is also provided.  
     A suspension stabilizer may be employed to reduce flocculation of the therapeutic substance within the composition. The composition may additionally include a polymer, such as, but not limited to, a bioabsorbable polymer, a biomolecule, or a biostable polymer.  
     A polymeric primer layer may be applied to the surface of the prosthesis prior to the application of the therapeutic composition. In addition, a polymeric topcoat disposed on at least a portion of the therapeutic composition on the surface of the prosthesis may be applied.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The present invention relates generally to implantable devices,examples of which include stents and grafts. More particularly, thepresent invention is directed to an improved method of coating animplantable device with a therapeutic substance.

[0003] 2. Description of the Related Art

[0004] Percutaneous transluminal coronary angioplasty (PTCA) is aprocedure for treating heart disease. A catheter assembly having aballoon portion is introduced percutaneously into the cardiovascularsystem of a patient via the brachial or femoral artery. The catheterassembly is advanced through the coronary vasculature until the balloonportion is positioned across the occlusive lesion. Once in positionacross the lesion, the balloon is inflated to a predetermined size toradially compress the atherosclerotic plaque of the lesion against theinner wall of the artery to dilate the lumen. The balloon is thendeflated to a smaller profile to allow the catheter to be withdrawn fromthe patient's vasculature.

[0005] A problem associated with the above procedure includes formationof intimal flaps or torn arterial linings which can collapse and occludethe vessel after the balloon is deflated. Moreover, thrombosis andrestenosis of the artery may develop over several months after theprocedure, which may require another angioplasty procedure or a surgicalby-pass operation. To reduce the partial or total occlusion of theartery by the collapse of arterial lining and to reduce the chance ofthe development of thrombosis and restenosis, a prosthesis, examples ofwhich include stents and grafts, is implanted.

[0006] Stents are scaffoldings, usually cylindrical or tubular in shape,which function to physically hold open and, if desired, to expand thewall of the vessel. Typically stents are capable of being compressed, sothat they may be inserted through small cavities via catheters, and thenexpanded to a larger diameter once they are at the desired location.Examples in patent literature disclosing stents which have been appliedin PTCA procedures include stents illustrated in U.S. Pat. No. 4,733,665issued to Palmaz, U.S. Pat. No. 4,800,882 issued to Gianturco, and U.S.Pat. No. 4,886,062 issued to Wiktor.

[0007] Synthetic vascular grafts are vessel-like configurations that maybe positioned into the host blood vessel as a replacement for a diseasedor occluded segment that has been removed. Alternatively, a graft may besutured to the host vessel at each end so as to form a bypass conduitaround a diseased or occluded segment of the host vessel.

[0008] Although stents and grafts are significant innovations in thetreatment of occluded vessels, there remains a need for administeringtherapeutic substances to the treatment site. To provide an efficaciousconcentration to the treatment site, systemic administration of thetherapeutic substance often produces adverse or toxic side effects forthe patient. Local delivery is a highly suitable method of treatment, inthat smaller levels of therapeutic substances, as compared to systemicdosages, are concentrated at a specific site. Local delivery producesfewer side effects and achieves more effective results.

[0009] One technique for the local delivery of therapeutic substances isthrough the use of medicated coatings on implantable devices. A commonmethod for medicating a prosthesis involves the use of a polymericcarrier coated onto the surface of the prosthesis. A composition isformed by dissolving a therapeutic substance in a solution containing apolymer and a solvent. The composition is applied to the prosthesisusing conventional techniques, such as spray-coating or dip-coating. Thesolvent is then removed, leaving on the prosthesis surface a coating ofthe polymer and the therapeutic substance impregnated in the polymer.

[0010] A shortcoming of the above-described method is the burst effect,in which an initial rapid release of therapeutic substance uponimplantation of the prosthesis is followed by a slower, sustainedrelease of therapeutic substance. Of the various factors whichcontribute to the burst effect, two factors stem from drying asolution-based coating. First, solution-based coating almost invariablyresults in an asymmetric distribution of therapeutic substance in thematrix. A higher concentration of therapeutic substance exists at thedrying surface, or polymer-air interface, since the therapeuticsubstance concentrates where the solvent was at the end of the dryingprocess. Additionally, a solvent-dried system may result in thetherapeutic substance being in an amorphous phase. When the therapeuticsubstance is amorphous, as opposed to crystalline, the therapeuticsubstance exists as individual molecules in the matrix. These moleculesmay diffuse freely without first having to dissolve into the matrix asthey would from a more crystalline phase and therefore contribute to theinitial burst of therapeutic substance upon implantation of theprosthesis.

[0011] Another shortcoming of the above-described method for medicatinga prosthesis is that the method does not facilitate processing everytherapeutic substance with every polymer and solvent combination. Sometherapeutic substances are very delicate and thus cannot tolerateprocessing in the presence of a solvent and or a polymer for extendedperiods of time. This is especially true for peptide-type therapeuticsubstances, such as actinomycin D and others, having tertiary structuresusceptible to transmutation from their native forms.

SUMMARY OF THE INVENTION

[0012] The present invention provides a method by which implantabledevices, such as stents and grafts, may be coated with therapeuticsubstances such that the burst effect and the transmutation of delicatetherapeutic substances are minimized.

[0013] In accordance with one embodiment of the present invention, amethod of forming a coating onto a surface of a prosthesis, such as astent or a graft, is provided. The method includes an act of providing acomposition including a therapeutic substance and a first fluid in whichthe therapeutic substance has limited solubility, such that thetherapeutic substance is suspended as particles in the composition. Themethod additionally includes the acts of applying the composition to asurface of the prosthesis and removing the first fluid from theprosthesis to form a coating. A coating for a prosthesis produced inaccordance with the above-described method is also provided.

[0014] In some embodiments of the method described herein, thecomposition additionally includes a second fluid capable of dissolvingthe therapeutic substance, and the act of providing a compositionincludes the acts of dissolving the therapeutic substance in the secondfluid to form a solution and combining the solution with the firstfluid. The therapeutic substance thus precipitates out of the solutionto form the composition in which the therapeutic substance is suspendedas particles. The act of removing the first fluid from the prosthesisalso removes the second fluid from the prosthesis.

[0015] In some embodiments of the above-described method, thecomposition additionally comprises a suspension stabilizer to minimizingflocculation of the therapeutic substance within the composition.

[0016] In other embodiments of the method, the composition additionallycomprises a polymer, such as but not limited to, a bioabsorbablepolymer, a biomolecule, or biostable polymer.

[0017] In still other embodiments, prior to the act of applying thecomposition to a surface of the prosthesis, the method further includesthe act of applying a polymeric primer layer to the surface of theprosthesis. The method may additionally include the act of creatingareas of roughness on the polymeric primer layer.

[0018] In other embodiments, subsequent to the acts of applying thecomposition to a surface of the prosthesis and removing the first fluidfrom the prosthesis, the method further includes the act of applying apolymeric topcoat disposed on at least a portion of the composition onthe surface of the prosthesis.

[0019] These and other aspects of the present invention may be betterappreciated in view of the detailed description and drawing of theexemplary embodiments.

BRIEF DESCRIPTION OF THE DRAWING

[0020]FIG. 1 is a flowchart illustrating a method of forming a coatingonto a surface of a prosthesis in accordance with the various disclosedembodiments.

DETAILED DESCRIPTION OF THE EMBODIMENTS Prosthesis

[0021] The prosthesis used in conjunction with the present invention maybe any implantable device, examples of which include self-expandablestents, balloon-expandable stents, and grafts, among otherpossibilities. The underlying structure of the prosthesis can bevirtually any design. The prosthesis can be made of a metallic materialor an alloy such as, but not limited to, stainless steel, “MP35N,”“MP20N,” ELASTINITE (Nitinol), tantalum, nickel-titanium alloy,platinum-iridium alloy, gold, magnesium, or combinations thereof.“MP35N” and “MP20N” are trade names for alloys of cobalt, nickel,chromium and molybdenum available from standard Press Steel Co.,Jenkintown, Pa. “MP35N” consists of 35% cobalt, 35% nickel, 20%chromium, and 10% molybdenum. “MP20N” consists of 50% cobalt, 20%nickel, 20% chromium, and 10% molybdenum. The prosthesis may also bemade from bioabsorbable or biostable polymers. A polymeric prosthesisshould be compatible with the composition.

Preparation of the Composition

[0022]FIG. 1 illustrates a method 100 of forming a coating onto asurface of the above-described prosthesis. The coating of the presentinvention is formed from a selected composition in which a therapeuticsubstance is suspended as particles. In act 101 of method 100, such acomposition is provided as described below.

[0023] In accordance with some embodiments, a predetermined amount of atherapeutic substance is added to a predetermined amount of a firstfluid. Of the total amount of therapeutic substance added to the firstfluid, from about 70% to 100%, or more particularly from about 95% to100%, of the therapeutic substance should be suspended as particles inthe first fluid and from 0% to about 30%, or more particularly from 0%to about 5% of the therapeutic substance may be in solution with thefirst fluid. Thus, the therapeutic substance has a limited solubility ofno more than 30% in the first fluid. When the prosthesis upon which thecoating is to be formed is a stent, the size of the suspended particlesof therapeutic substance can range from about 0.5 microns in diameter toabout 2 microns in diameter. When the prosthesis upon which the coatingis to be formed is a vascular graft, the size of the suspended particlesof therapeutic substance can range from about 0.5 microns in diameter toabout 20 microns in diameter, or more particularly from about 8 micronsin diameter to about 13 microns in diameter. The therapeutic substancecan be micronized to achieve such particle diameters.

[0024] In such embodiments, the therapeutic substance can make up fromabout 0.5% to about 30%, or more particularly from about 5% to about10%, by weight of the total weight of the composition, and the firstfluid can make up from about 70% to about 99.5%, or more particularlyfrom about 90% to about 95%, by weight of the total weight of thecomposition. Selection of a specific weight ratio is dependent onfactors such as the material from which the prosthesis to be coated ismade and the geometrical structure of the prosthesis as well as theparticular first fluid selected and various physical properties of theselected first fluid, such as contact angle, viscosity, and volatility.Selection of a specific weight ratio is also dependent on factors suchas the particular therapeutic substance selected, the duration of therelease, the cumulative amount of the release, and the release rate thatis desired

[0025] Therapeutic substances or agents suitable for inclusion in thecomposition include, but are not limited to, antineoplastic,antimitotic, antiinflammatory, antiplatelet, anticoagulant, antifibrin,antithrombin, antiproliferative, antibiotic, antioxidant, andantiallergic substances as well as combinations thereof. Examples ofsuch antineoplastics and/or antimitotics include paclitaxel (e.g.,TAXOL® by Bristol-Myers Squibb Co., Stamford, Conn.), docetaxel (e.g.,Taxotere® from Aventis S. A., Frankfurt, Germany) methotrexate,azathioprine, vincristine, vinblastine, fluorouracil, doxorubicinhydrochloride (e.g., Adriamycin® from Pharmacia & Upjohn, Peapack N.J.),and mitomycin (e.g., Mutamycin® from Bristol-Myers Squibb Co., Stamford,Conn.). Examples of such suitable antiinflammatories includeglucocorticoids such as dexamethasone, methylprednisolone,hydrocortisone and betamethasone and non-steroidal antiinflammatoriessuch as aspirin, indomethacin and ibuprofen. Examples of suchantiplatelets, anticoagulants, antifibrin, and antithrombins includesodium heparin, low molecular weight heparins, heparinoids, hirudin,argatroban, forskolin, vapiprost, prostacyclin and prostacyclinanalogues, dextran, D-phe-pro-arg-chloromethylketone (syntheticantithrombin), dipyridamole, glycoprotein IIb/IIIa platelet membranereceptor antagonist antibody, recombinant hirudin, and thrombininhibitors such as Angiomax™ (Biogen, Inc., Cambridge, Mass.) Examplesof such cytostatic or antiproliferative agents include actinomycin D aswell as derivatives and analogs thereof (manufactured by Sigma-Aldrich,Milwaukee, Wis.; or COSMEGEN® available from Merck & Co., Inc.,Whitehouse Station, N.J.), angiopeptin, angiotensin converting enzymeinhibitors such as captopril (e.g., Capoten® and Capozide® fromBristol-Myers Squibb Co., Stamford, Conn.), cilazapril or lisinopril(e.g., Prinivil® and Prinzide® from Merck & Co., Inc., WhitehouseStation, N.J.); calcium channel blockers (such as nifedipine),colchicine, fibroblast growth factor (FGF) antagonists, fish oil (omega3-fatty acid), histamine antagonists, lovastatin (an inhibitor ofHMG-CoA reductase, a cholesterol lowering drug, brand name Mevacor® fromMerck & Co., Inc., Whitehouse Station, N.J.), monoclonal antibodies(such as those specific for Platelet-Derived Growth Factor (PDGF)receptors), nitroprusside, phosphodiesterase inhibitors, prostaglandininhibitors, suranmin, serotonin blockers, steroids, thioproteaseinhibitors, triazolopyrimidine (a PDGF antagonist), and nitric oxide. Anexample of an antiallergic agent is permirolast potassium. Othertherapeutic substances or agents that may be used includealpha-interferon, genetically engineered epithelial cells, anddexamethasone. While the preventative and treatment properties of theforegoing therapeutic substances or agents are well-known to those ofordinary skill in the art, the substances or agents are provided by wayof example and are not meant to be limiting. Other therapeuticsubstances are equally applicable for use with the disclosed methods andcompositions.

[0026] In other embodiments, the therapeutic substance is a radioactiveisotope or a radiopaque substance. Such substances help to facilitateprosthesis usage in radiotherapeutic procedures. Examples of radioactiveisotopes include, but are not limited to, phosphoric acid (H₃P³²O₄),palladium (Pd¹⁰³), cesium (Cs¹³¹), and iodine (I¹²⁵). An example of aradiopaque substance is gold.

[0027] The first fluid should be a fluid in which the selectedtherapeutic substance is insoluble or in which the selected therapeuticsubstance has limited solubility, i.e., less than or equal to 30%, sincethe therapeutic substance must be primarily suspended as particles inthe first fluid rather than dissolved in the first fluid. Exposure ofthe therapeutic substance to the first fluid is not permitted toadversely alter the substance's composition or characteristic.Accordingly, the particular first fluid is selected for chemicalcompatibility with the selected therapeutic substance. The particularfirst fluid selected also depends on the material of which theprosthesis is made. For example, if the prosthesis is made of anabsorbable polymer, caution should be exercised in the selection of allfluids since some absorbable polymers of which a prosthesis can be madedissolve in fluids that are otherwise suitable for usage in the presentinvention. In addition, the first fluid should have a high volatility aswell as a low contact angle. Exemplary first fluids include, but are notlimited to, deionized water, methanol, ethanol, freon, and acetonitrile.

[0028] In some embodiments, the composition additionally includes apolymer, or a combination of polymers, dissolved in the first fluid. Thepolymeric material is most suitably biocompatible, including polymersthat are non-toxic, non-inflammatory, chemically inert, andsubstantially non-immunogenic in the applied amounts. The polymer istypically either bioabsorbable or biostable. A bioabsorbable polymerbreaks down in the body and is not present sufficiently long afterimplantation to cause an adverse local response. Bioabsorbable polymersare gradually absorbed or eliminated by the body by hydrolysis,metabolic process, bulk, or surface erosion. Examples of bioabsorbablematerials include but are not limited to polycaprolactone (PCL), poly-D,L-lactic acid (DL-PLA), poly-L-lactic acid (L-PLA),poly(lactide-co-glycolide), poly(hydroxybutyrate),poly(hydroxybutyrate-co-valerate), polydioxanone, polyorthoester,polyanhydride, poly(glycolic acid), poly(glycolic acid-cotrimethylenecarbonate), polyphosphoester, polyphosphoester urethane, poly (aminoacids), cyanoacrylates, poly(trimethylene carbonate),poly(iminocarbonate), copoly(ether-esters), polyalkylene oxalates,polyphosphazenes, polyiminocarbonates, and aliphatic polycarbonates.Biomolecules such as heparin, fibrin, fibrinogen, cellulose, starch, andcollagen are typically also suitable. A biostable polymer does not breakdown in the body, and thus a biostable polymer is present in the bodyfor a substantial amount of time after implantation. Examples ofbiostable polymers include Parylene®, Parylast®, polyurethane (forexample, segmented polyurethanes such as Biospan®), polyethylene,polyethlyene teraphthalate, ethylene vinyl acetate, silicone,polyethylene oxide, and polytetrafluoroethylene (PTFE).

[0029] In such embodiments, the polymeric material can make up fromabout 0.1% to about 30%, or more particularly from about 0.1% to about10%, by weight of the total weight of the composition, the therapeuticsubstance can make up from about 0.5% to about 30%, or more particularlyfrom about 0.5% to about 10%, by weight of the total weight of thecomposition, and the first fluid can make up from about 40% to about99.4%, or more particularly from about 80% to about 99.4%, by weight ofthe total weight of the composition. In addition to the factorsdiscussed above, selection of a specific weight ratio is dependent onfactors such as the particular polymer, or combination of polymers,selected and the solubility of the selected polymer in the selectedfirst fluid.

[0030] In other embodiments, the therapeutic substance is not initiallysuspended in the first fluid. Rather, the therapeutic substance is firstdissolved in a second fluid to form a solution. The second fluid,therefore, must be selected to be a good solvent for the selectedtherapeutic substance. The above-described first fluid is then slowlyadded into the therapeutic substance-containing solution. This processprecipitates the therapeutic substance from the composition such that afine colloidal system is formed in situ. The resulting suspension of thetherapeutic substance has a very controlled particle size distribution.The size of the suspended particles of therapeutic substance can rangefrom about 0.5 microns in diameter to about 20 microns in diameter, ormore particularly from about 0.5 microns in diameter to about 5 micronsin diameter.

[0031] In such embodiments, the solvent or second fluid can make up fromabout 50% to about 99%, or more particularly from about 70% to about99%, by weight of the total weight of the composition, the therapeuticsubstance can make up from about 0.5% to about 30%, or more particularlyfrom about 0.5% to about 10%, by weight of the total weight of thecomposition, and the first fluid can make up from about 0.5% to about20%, or more particularly from about 0.5% to about 10%, by weight of thetotal weight of the composition. Selection of a specific weight ratio isdependent on factors such as the material from which the prosthesis tobe coated is made and the geometrical structure of the prosthesis aswell as the particular first and second fluids selected and variousphysical properties of the selected first and second fluids, such ascontact angle, viscosity, and volatility. Selection of a specific weightratio is also dependent on factors such as the particular therapeuticsubstance selected, the duration of the release, the cumulative amountof the release, and the release rate that is desired.

[0032] In some embodiments in which the therapeutic substance isdissolved in a second fluid prior to being suspended in the first fluid,the composition additionally includes a polymer or a combination ofpolymers dissolved in the second fluid. Examples of such polymericmaterials were listed above, and such examples are equally applicablehere. In such embodiments, the polymeric material can make up from about0.1% to about 30%, or more particularly from about 0.1% to about 10%, byweight of the total weight of the composition, the solvent or secondfluid can make up from about 20% to about 89.9%, or more particularlyfrom about 70% to about 89.9%, by weight of the total weight of thecomposition, the therapeutic substance can make up from about 0.5% toabout 30%, or more particularly from about 0.5% to about 10%, by weightof the total weight of the composition, and the first fluid can make upfrom about 0.5% to about 20%, or more particularly from about 0.5% toabout 10%, by weight of the total weight of the composition. Typically,the first fluid should not precipitate the polymer from the secondfluid.

[0033] In still other embodiments of the composition, a suspensionstabilizer is added to minimize flocculation. Flocculation refers to theclumping and/or settling of suspended particles. In this particularinstance, flocculation refers to the clumping and/or settling oftherapeutic substance particles in the composition. Exemplarydeflocculants include, but are not limited to, pluronic, polyvinylalcohol (PVA), and stearates. Typically, the stabilizer makes up fromabout 0.1% to about 1% by weight of the total weight of the composition.

Coating the Prosthesis Using the Composition

[0034] To form a coating on a surface of the prosthesis, the surface ofthe prosthesis should be clean and free from contaminants that may beintroduced during manufacturing. Other than cleaning, the surface of theprosthesis requires no particular surface treatment to retain theapplied coating, although the surface may optionally be subjected tophysical treatments, such as, but not limited to, the creation of depotsin the surface of the prosthesis, to maximize retention of the coating.

[0035] Referring again to FIG. 1, the above-described compositionprovided in act 101 of method 100 is applied to the prosthesis in act102. Care should be taken to ensure that the particles of therapeuticsubstance are suspended in the composition, as opposed to settled at thebottom of the composition, prior to the application of the compositionto the prosthesis. The addition of a suspension stabilizer to thecomposition, as described above, can aid in the prevention of settlingof therapeutic substance particles. The composition may also be vortexedfor approximately 5-30 seconds just prior to application to theprosthesis to ensure proper suspension of the therapeutic substance.

[0036] The above-described composition maybe applied to the surface of aprosthesis in act 102 by any conventional method, such as by sprayingthe composition onto the prosthesis or immersing the prosthesis in thecomposition. Variations of spray and immersion techniques are alsosuitable methods of applying the composition to a surface of aprosthesis. In one such variation, the composition may be applied byspraying or immersing the prosthesis as described above. Thecomposition-coated prosthesis is then centrifuged. The rotation of theprosthesis creates a centrifugal force upon the composition applied tothe surface of the prosthesis. This centrifugal force causes excessaccumulations of the composition to be more evenly redistributed overthe prosthesis and thus provides a more even, uniform coating of thecomposition on the prosthesis. The rotational speed duringcentrifugation can be varied. Higher RPM values may provide improveduniformity and a reduction in defects. However, lower RPM values improvethe total loading of the composition onto the prosthesis. Increasing thetotal centrifugation time may also improve the uniformity and reducedefects in the coating of the composition on the prosthesis.

[0037] The act 102 of applying the composition to the prosthesis isfollowed by the removal of the first fluid and any second fluid from thecomposition on the prosthesis in act 103. The first and second fluidsmay be removed using techniques such as evaporation at ambient pressureand room temperature in an anhydrous atmosphere for 48 hours, orexposure to mild heat, e.g., 60-65° C., under vacuum conditions. Inexamples wherein the prosthesis is made of an absorbable polymer, thefirst and second fluids should be removed relatively quickly to avoidprolonged exposure and thereby ensure the mechanical integrity of theabsorbable prosthesis. Upon removal of essentially all of the firstfluid and any second fluid, a coating remains on the prosthesis.

[0038] In some embodiments, a polymeric coating, without a therapeuticsubstance, is applied to the prosthesis in act 104 prior to theapplication of the composition to the prosthesis in act 102. Thepolymeric layer can serve as a primer to facilitate better adhesion ofthe composition to the prosthesis and is particularly useful when thecomposition does not itself contain polymeric material. Examples ofsuitable polymers were listed above, and such examples are equallyapplicable here. The polymeric primer can be formed on the prosthesis byany conventional method, such as the immersion or spray techniquesdescribed above. By way of example, and not limitation, the polymericprimer can have a thickness of about 0.5 microns to about 2.0 microns.The particular thickness of the layer is dependent on the desired use ofthe primer and the type of procedure for which the prosthesis isemployed. The primer layer should be dried in act 105 prior to theapplication of the composition onto the primer layer in act 101. Suchdrying may be accomplished using conventional methods known to one ofordinary skill in the art, such as those described above with referenceto the drying of the composition in act 103.

[0039] In some embodiments in which a primer is utilized, asperities, orareas of roughness, are created on the polymeric layer in act 106. Theasperities enable the primer layer to physically entrap the therapeuticsubstance-containing composition that is subsequently applied atop theprimer layer in act 102. A variety of methods can be used to create theasperities on the primer layer covering the outer surface of theprosthesis.

[0040] In one method, a pressurized stream of grit material is directedupon the polymeric primer layer after the primer layer has been dried inact 105. Examples of such processes include bead blasting and sandblasting. Bead blasting refers to the use of pressurized gas to projectbeads of a relatively uniform diameter at an object at a high velocity.The beads may be made of materials such as, but not limited to, aluminumoxide, silicon oxide, or latex. In sand blasting, the grit projecteddoes not have as uniform a diameter as in bead blasting. Both beadblasting and sand blasting are techniques that are well known to thoseof ordinary skill in the art. The roughness achieved using a pressurizedgrit source can be controlled by the size of the grit, e.g., thediameter of the beads, the pressure used, the distance between the gritsource and the primer surface, and the length of time the grit isblasted at the primer surface. By way of example and not limitation, thegrit can be beads having a diameter of between 10 μm and 50 μm.Pressures of 30 PSI (pounds per square inch) to 60 PSI can be used toproject the beads from a distance of approximately 3-10 cm from theprosthesis.

[0041] In another embodiment, laser etching is used to create asperitieson the primer layer after the primer layer has been dried in act 105.Laser lithographic methods are known to those of ordinary skill in theart. A laser is directed onto the primer layer for a predeterminedperiod of time, which depends on the etch rate and the depth of etchdesired. A patterned mask that has openings may be applied over theprimer layer before the laser is utilized. The laser is then allowed toetch the primer through the openings of the mask. The use of patternedmasks with laser etching is known to those of ordinary skill in the art.

[0042] In another embodiment, the manner in which the primer isdeposited onto the outer surface of the prosthesis in act 104 can createthe asperities required in act 106. The primer may be added via physicaldeposition processes, for example, sputtering, which is known to thoseof ordinary skill in the art. In sputtering, an energy beam, forinstance an ion beam, is directed at a target formed of the materialwhich is to be deposited on the substrate. The energy beam dislodgesatoms of the target material. The target material atoms are transportedto the substrate, which in this instance is the primer-coated stent onwhich asperities are being formed. Once at the substrate, the atoms form“islands”, or small nodules of the deposition material on the substrate.

[0043] Conventionally, sputtering is used to form a thin film of thedeposition material over the substrate, and sputtering conditions areused such that the “islands” grow, spread, and condense on the substrateto form a thin film. To form the asperities, however, the sputteringconditions are set so that instead of creating a uniform film over thesubstrate, the “islands” do not grow, spread, and condense, leaving arough surface. Process conditions in which a lower pressure and shorterdeposition time than is typically used for thin film deposition are usedto form the asperities in the primer layer in still another embodiment,a polymeric coating, without a therapeutic substance, is deposited inact 107 on the composition-based coating applied in act 102. Thepolymeric topcoat can be applied by any conventional method, such as theimmersion or spray techniques described above. The polymeric topcoatproduces a membrane that reduces the rate of release of the therapeuticsubstance or substances from the composition-based coating. Examples ofsuitable polymers were listed above, and such examples are equallyapplicable here. By way of example, and not limitation, the polymerictopcoat can have a thickness of about 0.25 microns to about 1.5 microns.Typically, the topcoat can have a thickness of about 1 micron. It isunderstood by one of ordinary skill in the art that the thickness of thepolymeric overlayer is based on factors such as the type of procedurefor which the prosthesis is employed and the rate of release that isdesired. The topcoat should be dried in act 108. Such drying may beaccomplished using conventional methods known to one of ordinary skillin the art, such as those described above with reference to the dryingof the composition in act 103.

[0044] In still another embodiment, both a polymeric primer and apolymeric topcoat are employed via acts 104 and 107, respectively. Inthis embodiment, a polymeric primer is applied to a clean prosthesisprior to the application of the composition as described above. Afterthe primer layer has been dried, the composition is applied atop thedried primer layer. The polymeric topcoat is applied and dried in acts107 and 108, respectively, subsequent to the application and drying ofthe composition in acts 102 and 103, respectively. Such an embodimentfacilitates the initial immobilization of the therapeutic substance onthe prosthesis followed by the controlled release of the therapeuticsubstance.

Methods of Use

[0045] An implanted stent or graft, having the above-describedtherapeutic coating, is useful for treating occluded regions of bloodvessels caused by thrombosis and/or restenosis, among other possibleuses.

[0046] Stents may be placed in a wide array of blood vessels, botharteries and veins. Briefly, an angiography is first performed todetermine the appropriate positioning for stent therapy. Angiography istypically accomplished by using a catheter to inject a radiopaquecontrasting agent into an artery or vein as an X-ray is taken. Aguidewire is then advanced through the lesion or proposed site oftreatment. Over the guidewire is passed a delivery catheter which allowsa stent in its collapsed configuration to be inserted into thepassageway. The delivery catheter is inserted either percutaneously orby surgery into the femoral artery, brachial artery, femoral vein, orbrachial vein and advanced into the appropriate blood vessel by steeringthe catheter through the vascular system under fluoroscopic guidance. Astent having the above described covering may then be expanded at thedesired area of treatment. A post-insertion angiograrn may also beutilized to confirm appropriate positioning.

[0047] Vascular grafts may be used to replace, bypass, or reinforcediseased or damaged sections of a vein or artery. The general procedurefor implantation includes the step of pre-clotting, wherein the graft isimmersed in the blood of the patient and allowed to stand for a periodof time sufficient for clotting to ensue. After pre-clotting,hemorrhaging is less likely to occur when the graft is implanted, andthus the growth of tissue is not impeded. Grafts may be placed eitherthrough invasive surgery or non-invasively through percutaneousendoluminal transport. Percutaneous delivery of a graft avoids thecomplications and risks of surgery. The graft may be attached to thevessel at each end of the diseased region, thus bypassing the diseasedregion. Alternatively, the diseased region may be removed and replacedby the graft.

EXAMPLES

[0048] Exemplary embodiments of the invention are illustrated below.These examples are being given by way of illustration only and not byway of limitation. The parameters given, including percentages offluids, therapeutic substance, polymers, temperature, duration of time,and other data, are exemplary, not limiting.

Example 1

[0049] The following is an exemplary method in which the compositionincludes a therapeutic substance and a first fluid. A polymeric primerlayer and a polymeric topcoat are also employed.

[0050] Multi-Link Duet™ stents (available from Guidant Corporation) werecleaned by placement in an ultrasonic bath of isopropyl alcohol solutionfor 10 minutes. The stents were air-dried. A primer coating of ethylenevinyl alcohol copolymer (EVOH) was made with 1 gram of EVOH and 5 gramsof dimethyl sulfoxide (DMSO), yielding an EVOH:DMSO ratio of 1:5. TheEVOH was dissolved by placing the vial of EVOH:DMSO solution on a rollerbottle apparatus in an oven at 60° C. for 6 hours. The EVOH:DMSOsolution was sprayed onto the cleaned Multi-Link Duet™ stents. Theprimer-coated stents were placed in a oven at 60° C. for 4 hours.

[0051] A 5% suspension of actinomycin D was made by dissolving 0.05 gramof actinomycin D in 1 gram of methanol. The primer-coated stents weredipped into the suspension for 5 seconds. The actinomycin D-coatedstents were then air-dried for 15 minutes.

[0052] An EVOH topcoating, which was prepared as the primer coatingabove, was sprayed onto the actinomycin D-coated stents. The coatedstents were placed in a convection oven at 50° C. for 4 hours. Theaverage amount of actinomycin D retained on the stents was about 39micrograms.

Example 2

[0053] The following is another exemplary method in which thecomposition includes a therapeutic substance and a first fluid. Apolymeric primer layer and a polymeric topcoat are also employed.

[0054] Multi-Link Duet™ stents were cleaned by placement in anultrasonic bath of isopropyl alcohol solution for 10 minutes. The stentswere air-dried. A primer coating of EVOH was made with 1 gram of EVOHand 7 grams of DMSO, yielding an EVOH:DMSO ratio of 1:7. The EVOH wasdissolved by placing the vial of EVOH:DMSO solution on a roller bottleapparatus in an oven at 60° C. for 6 hours. The EVOH:DMSO solution wasapplied to the cleaned Multi-Link Duet™ stents by a modified dip method.The primer-coated stents were placed in a oven at 60° C. for 4 hours.

[0055] A 5% suspension of actinomycin D was made by dissolving 0.05 gramof actinomycin D in 1 gram of methanol. The primer-coated stents weredipped into the suspension for 5 seconds. The actinomycin D-coatedstents were then air-dried for 15 minutes.

[0056] An EVOH topcoating, which was prepared as the primer coatingabove, was sprayed onto the actinomycin D-coated stents. The coatedstents were placed in a convection oven at 50° C. for 4 hours. Theaverage amount of actinomycin D retained on the stents was about 15micrograms.

Example 3

[0057] The following is an exemplary method in which the compositionincludes a therapeutic substance, a first fluid, a polymer, and asuspension stabilizer.

[0058] A Multi-Link Duet™ stent is cleaned by placement in an ultrasonicbath of isopropyl alcohol solution for 10 minutes. The stent isair-dried. An EVOH:DMSO solution is made with 1 gram of EVOH and 4 gramsof DMSO, making a solution having a EVOH:DMSO ratio of 1:4. ActinomycinD is added to the EVOH:DMSO solution to form a suspension. Actinomycin Dconstitutes 10% by weight of the total weight of the suspension.Pluronic, a suspension stabilizer, is added to the suspension to slowthe flocculation rate of the suspended actinomycin D particles. Thesuspension stabilizer constitutes 0.5% by weight of the total weight ofthe suspension. The suspension is vortexed for 10 seconds. The viscosityof the EVOH:DMSO solution is adequate to slow the flocculation rate ofthe suspended actinomycin D particles for approximately 30 minutes. Thecleaned Multi-Link Duet™ stent is attached to mandrel wires and dippedinto the suspension. The coated stent is then placed in a vacuum oven at60° C. for 24 hours. It is predicted that the coating will remain intacton the stent.

Example 4

[0059] The following is an exemplary method in which the compositionincludes a therapeutic substance, a first fluid, a second fluid, and apolymer A Multi-Link Duet™ stent is cleaned by placement in anultrasonic bath of isopropyl alcohol solution for 10 minutes. The stentis air-dried. An actinomycin D:tetrahydrofuran (THF) solution is madewith 0.32 gram of actinomycin D and 4 grams of THF, making a solutionhaving an actinomycin D:tetrahydrofuran (THF) ratio of 2:23. AnEVOH:DMSO solution is made with 1 gram of EVOH and 4 grams of DMSO,making a solution having a EVOH:DMSO ratio of 1:4. The EVOH:DMSOsolution is gradually added into the actinomycin D:THF solution. Thisprocess precipitates the actinomycin D from the actinomycin:THFsolution. Actinomycin D constitutes 3.4% by weight of the total weightof the suspension. The suspension is vortexed for 10 seconds. Theviscosity of the EVOH:DMSO:THF solution is adequate to slow theflocculation rate of the suspended actinomycin D particles. The cleanedMulti-Link Duet™ stent is attached to mandrel wires and dipped into thesuspension. The coated stent is then placed in a vacuum oven at 60° C.for 24 hours. It is predicted that the coating will remain intact on thestent.

Example 5

[0060] The following is an exemplary method in which the compositionincludes a therapeutic substance, a first fluid, and a suspensionstabilizer. A polymeric primer layer is also employed.

[0061] A synthetic graft made from polytetrafluoroethylene (PTFE) iscleaned by placement in an ultrasonic bath of isopropyl alcohol solutionfor 10 minutes. The graft is air-dried. An EVOH solution is made with 1gram of EVOH and 7 grams of DMSO, making an EVOH:DMSO ratio of 1:7. Themixture is placed in a warm water shaker bath at 60° C. for 24 hours.The solution is cooled and vortexed. The cleaned graft is dipped in theEVOH:DMSO solution. The coated graft is then placed in a oven at 60° C.,under vacuum condition, and for 24 hours. The coating will provide aprimer layer to facilitate adhesion of the following actinomycin Dlayer.

[0062] A suspension of actinomycin D in DMSO:THF:EVAL is made with 0.32gram of actinomycin D and 9 grams of DMSO:TBF:EVAL, such thatactinomycin D constitutes 3.4% by weight of the total weight of thesuspension. The suspension is vortexed for 10 seconds. Pluronic, asuspension stabilizer, is added to the suspension to slow theflocculation rate of the suspended actinomycin D particles. Thesuspension stabilizer constitutes 0.5% by weight of the total weight ofthe suspension. The primer-coated graft is attached to mandrel wires anddipped into the suspension. The coated graft is then placed in a vacuumoven at 60° C. for 24 hours. It is predicted that the coatings willremain intact on the graft.

Example 6

[0063] The following is an exemplary method in which the compositionincludes a therapeutic substance and a first fluid. A polymeric topcoatis also employed.

[0064] A stent having cavities formed in the surface thereof is cleanedby placement in an ultrasonic bath of isopropyl alcohol solution for 10minutes. The stent is air-dried. Cisplatin is micronized using a mortarand pestle assembly to yield particles ranging in size from 1-2 microns.A suspension of cisplatin in dimethyl formamide (DMF) is made such thatcisplatin constitutes 5% by weight of the total weight of thesuspension. The suspension is vortexed vigorously for 10 seconds toprevent flocculation. The cleaned stent is attached to mandrel wires anddipped into the suspension. The excess suspension is removed by lightlytouching a highly porous, lint-free cloth to the stent for 30 seconds.

[0065] The cisplatin-coated stent is dipped into a 1:4 EVOH:DMSOsolution, free from cisplatin. The stent is placed in the oven to dry aspreviously described. The top coating will provide a barrier layer forcontrolling the release of cisplatin from the cisplatin layer. It ispredicted that the coatings will remain intact on the stent.

Example 7

[0066] The following is an exemplary method in which the compositionincludes a therapeutic substance and a first fluid. A polymeric primerlayer and a polymeric topcoat are also employed.

[0067] A Multi-Link Duet™ stent is cleaned by placement in an ultrasonicbath of isopropyl alcohol solution for 10 minutes. The stent isair-dried. An EVOH:DMSO solution is made with 1 gram of EVOH and 7 gramsof DMSO, making an EVOH:DMSO ratio of 1:7. The mixture is placed in awarm water shaker bath at 60° C. for 24 hours. The solution is cooledand vortexed. The cleaned Multi-Link Duet™ stent is dipped in theEVOH:DMSO solution. The EVOH-coated stent is placed in a oven at 60° C.,under vacuum condition, and for 24 hours. The coating will provide aprimer layer for the following cisplatin layer.

[0068] Cisplatin is micronized using a mortar and pestle assembly toyield particles ranging in size from 1-2 microns. A suspension ofcisplatin in dimethyl formamide (DMF) is made such that cisplatinconstitutes 5% by weight of the total weight of the suspension. Thesuspension is vortexed vigorously for 10 seconds to preventflocculation. The primer-coated stent is attached to mandrel wires anddipped into the suspension. The excess suspension is removed by lightlytouching a highly porous, lint-free cloth to the stent for 30 seconds.

[0069] The cisplatin-coated stent is dipped into a 1:4 EVOH:DMSOsolution, free from cisplatin. The stent is placed in the oven to dry aspreviously described. The top coating will provide a barrier layer forcontrolling the release of cisplatin from the cisplatin layer. It ispredicted that the coatings will remain intact on the stent.

Example 8

[0070] The following is an another exemplary method in which thecomposition includes a therapeutic substance and a first fluid. Apolymeric primer layer and a polymeric topcoat are also employed.

[0071] A synthetic graft made from expanded polytetrafluoroethylene(ePTFE) is cleaned by placement in an ultrasonic bath of isopropylalcohol solution for 10 minutes. The graft is air-dried. An EVOH:DMSOsolution is made with 1 gram of EVOH and 7 grams of DMSO, making anEVOH:DMSO ratio of 1:7. The mixture is placed in a warm water shakerbath at 60° C. for 24 hours. The solution is cooled and vortexed. Thecleaned graft is dipped in the EVOH:DMSO solution. The EVOH-coated graftis placed in a oven at 60° C., under vacuum condition, and for 24 hours.The coating will provide a primer layer for the following cisplatinlayer.

[0072] Cisplatin is micronized using a mortar and pestle assembly toyield particles ranging in size from 1-2 microns. A suspension ofcisplatin in methanol is made such that cisplatin constitutes 5% byweight of the total weight of the suspension. The suspension is vortexedvigorously to prevent flocculation. The primer-coated graft is dippedinto the suspension. The excess suspension is removed by lightlytouching a highly porous, lint-free cloth to the stent for 30 seconds.

[0073] The cisplatin-coated graft is dipped into a 1:4 EVOH:DMSOsolution, free from cisplatin. The graft is placed in the oven to dry aspreviously described. The top coating will provide a barrier layer forcontrolling the release of cisplatin from the cisplatin layer. It ispredicted that the coatings will remain intact on the graft.

[0074] While particular embodiments, applications, and examples of thepresent invention have been shown and described, it will be apparent tothose of ordinary skill in the art that changes and modifications can bemade without departing from this invention in its broader aspects.Therefore, the appended claims are to encompass within their scope allsuch changes and modifications as fall within the true spirit and scopeof this invention.

What is claimed is:
 1. A method of forming a coating onto a surface ofan implantable prosthesis, the method comprising the acts of: (a)providing a composition comprising a therapeutic substance and a firstfluid in which said therapeutic substance has limited solubility, saidtherapeutic substance being suspended as particles in said composition;(b) applying said composition to a surface of said prosthesis; and (c)removing said first fluid from said prosthesis to form a coating.
 2. Acoating for an implantable prosthesis produced in accordance with themethod of claim
 1. 3. The method of claim 1, wherein said prosthesis isselected from a group of balloon-expandable stents, self-expandablestents, and grafts.
 4. The method of claim 1, wherein about 50% to 100%of said therapeutic substance is suspended as particles in saidcomposition.
 5. The method of claim 1, wherein said particles of saidtherapeutic substance have diameters ranging from about 3 microns toabout 20 microns.
 6. The method of claim 1, wherein said therapeuticsubstance is selected from a group of antineoplastic, antimitotic,antiinflammatory, antiplatelet, anticoagulant, antifibrin, antithrombin,antiproliferative, antibiotic, antioxidant, and antiallergic substancesand combinations thereof.
 7. The method of claim 1, wherein saidtherapeutic substance is selected from a group of radioactive isotopesand radiopaque substances.
 8. The method of claim 1, wherein saidtherapeutic substance comprises from about 0.5% to about 30% by weightof the total weight of said composition and said first fluid comprisesfrom about 70% to about 99.5% by weight of the total weight of saidcomposition.
 9. The method of claim 1, wherein said compositionadditionally comprises a suspension stabilizer, said suspensionstabilizer reducing flocculation of said therapeutic substance withinsaid composition
 10. The method of claim 1, wherein said compositionadditionally comprises a polymer.
 11. The method of claim 9, whereinsaid polymer is selected from a group of bioabsorbable polymers,biomolecules, and biostable polymers.
 12. The method of claim 10,wherein said polymer comprises from about 0.1% to about 30% by weight ofthe total weight of said composition, said therapeutic substancecomprises from about 0.5% to about 30% by weight of the total weight ofsaid composition, and said first fluid comprises from about 40% to about99.4% by weight of the total weight of said composition.
 13. The methodof claim 1, wherein prior to said act of applying said composition to asurface of said prosthesis, the method further comprises the act of:applying a polymeric primer layer to said surface of said prosthesis.14. The method of claim 13, wherein said polymeric primer layer has athickness ranging from about 0.5 microns to about 2 microns.
 15. Themethod of claim 13, wherein said method further comprises the act of:creating areas of roughness on said polymeric primer layer.
 16. Themethod of claim 15, wherein said act of creating areas of roughness onsaid polymeric primer layer comprises the act of: directing apressurized stream of a grit material upon said polymeric primer layer.17. The method of claim 15, wherein said act of creating areas ofroughness on said polymeric primer layer comprises the act of: laseretching said polymeric primer layer.
 18. The method of claim 15, whereinsaid act of creating areas of roughness on said polymeric primer layercomprises the act of: sputtering polymeric material onto said surface ofsaid prosthesis to form said areas of roughness.
 19. The method of claim1, wherein subsequent to said acts of applying said composition to asurface of said prosthesis and removing said first fluid from saidprosthesis, the method further comprises the act of: applying apolymeric topcoat disposed on at least a portion of said composition onsaid surface of said prosthesis.
 20. The method of claim 19, whereinsaid polymeric topcoat has a thickness ranging from about 0.25 micronsto about 1.5 microns.
 21. The method of claim 1, wherein saidcomposition additionally comprises a second fluid capable of dissolvingsaid therapeutic substance and wherein said act of providing acomposition comprises the acts of: dissolving said therapeutic substancein said second and fluid to form a solution; and combining said solutionwith said first fluid, wherein said therapeutic substance precipitatesout of said solution to form said composition in which said therapeuticsubstance is suspended as particles; and wherein said act of removingsaid first fluid from said prosthesis also removes said second fluidfrom said prosthesis.
 22. The method of claim 21, wherein said secondfluid comprises from about 50% to about 99% by weight of the totalweight of said composition, said therapeutic substance comprises fromabout 0.5% to about 30% by weight of the total weight of saidcomposition, and said first fluid comprises from about 0.5% to about 20%by weight of the total weight of said composition.
 23. The method ofclaim 21, wherein said composition additionally comprises a polymer. 24.The method of claim 23, wherein said polymer comprises from about 0.1%to about 30% by weight of the total weight of said composition, saidsecond fluid comprises from about 20% to about 89.9% by weight of thetotal weight of said composition, said therapeutic substance comprisesfrom about 0.5% to about 30% by weight of the total weight of saidcomposition, and said first fluid comprises from about 0.5% to about 20%by weight of the total weight of said composition.
 25. The method ofclaim 21, wherein prior to said act of applying said composition to asurface of said prosthesis, the method further comprises the act of:applying a polymeric primer layer to said surface of said prosthesis.26. The method of claim 25, wherein subsequent to said acts of applyingsaid composition to a surface of said prosthesis and removing said firstfluid and said second fluid from said prosthesis, the method furthercomprises the act of: applying a polymeric topcoat disposed on at leasta portion of said composition on said surface of said prosthesis.